Targeted drug delivery results in significant clinical benefits for disease treatment, especially for cancer. Encapsulation of cytotoxic anticancer drugs inside a nanoparticle is able to decrease side toxicity and improve the life quality of patient. In addition, passive or active targeting effect of the nanocarrier is able to deliver significantly high dose of chemodrugs to tumors and yields improved cancer treatment or even cure of the disease. Stability, drug loading capacity, reproducibility and biocompatibility are critical for the clinical translation of all drug delivery systems.
Combination chemotherapy involves using two or more drugs proven effective against a tumor type. As a treatment strategy it has accounted for major advances in cancer treatment, in part because it helps overcome the rapid development of drug resistance by tumor cells and implicitly addresses the heterogeneity of cancer cells and that at any given time individual cells making up a tumor will be in different phases of the cell cycle. Cell-cycle specific and cell-cycle non-specific drugs are given in combination, because the cell-cycle specific drugs reduce the tumor growth factor, and cell-cycle non-specific drugs help to reduce the tumor burden. In addition, combining drugs can decrease the incidence and severity of side effects of therapy.
For example, Cisplatin (CDDP) and paclitaxel (PTX) are two of the most popular chemotherapeutic drugs used in combination for the treatment of many cancers, including rarely curable ovarian cancers. CDDP binds DNA and inhibits DNA synthesis; while PTX arrests the cell cycle by stabilizing microtubules. Given their distinct mechanisms of action, it has been demonstrated that co-administration of CDDP and PTX can achieve synergistic effects on tumor cells. Interestingly, PTX shows strong synergism when it is administered first; however, it shows antagonistic effects when administered after CDDP in ovarian cancer patients. Although PTX is ˜1000 times more potent than CDDP (IC50s: low nM vs low μM) in a wide variety of cancer cells in culture, a much higher dose of PTX (175 mg/m2 every three weeks) than CDDP (75-100 mg/m2 every four weeks) can be used for cancer treatment. This reflects the relative low systemic toxic side effects of PTX vs. CDDP, due to the fast in vivo clearance and metabolizing of organic PTX as compared with the heavy metal drug CDDP. On the other hand, the poor pharmacokinetics (t1/2 in human: 0.34 hours (h)) and pharmacodynamic profiles (cytochrome P450 metabolism) of PTX may limit its accumulation in the tumor and hinder its in vivo potency. In contrast, CDDP dominantly binds to serum proteins and is eliminated and metabolized much slower in vivo. The dissociated CDDP and its metabolites lead to long-term drug exposure of tumor cells, as well as normal tissues. As a result, CDDP is one of the most active anticancer drugs, albeit with significant acute and chronic nephro-, oto-, and peripheral neuro-toxicity. Therefore, it is important for a PTX-based combination therapy to increase PTX bioavailability and drug exposure to tumor cells. Combination therapies employing CDDP as one of the drugs will be improved if the acute and chronic toxic side effects of CDDP are diminished. An optimal PTX/CDDP combination therapy should do both as well as administering or releasing the two drugs such that a synergistic effect on tumor cells is achieved.
Another combination therapy uses Doxorubicin (DOX) and Bortezomib (BTZ), which are chemo-drugs commonly used to treat various forms of cancers, such as multiple myeloma and lymphoma. Proteasome inhibitors (bortezomib) and immunomodulators (Lenalidomide (LLD) and analogues) have been used effectively in treating newly diagnosed MM patients in combination with other chemodrugs, e.g., doxorubicin (DOX), dexamethasone (DEX) and melphalan. Studies indicate that angiogenesis also plays an important role in the cancer progression in localized MM and lymphoma. Anti-angiogenesis drugs, such as LLD and its analogues, have shown clinical activities in treating MM. Active tumoral angiogenesis leads to leaky blood vessel formation, which provides a great opportunity for MM or lymphoma-targeted drug delivery using NPs via the EPR effects. In line with these findings, liposomal doxorubicin has been approved to treat relapsed or refractory MM in combination with BZB. However, current combination treatments have side toxicity issues. MM remains rarely curable. New drugs and novel treatments are still needed for the intensive as well as the maintenance treatment of MM. The cell-adhesion-mediated drug resistance (CAM-DR) of MM cells in BM led to resistance to the first line anticancer drugs, such as DOX. Interestingly, studies showed that bortezomib (BZB) can overcome CAM-DR through down-regulation of VLA-4 expression in MM and enhance the effects of conventional anti-myeloma therapeutics. Better combination therapies with fewer side effects and higher efficacy using DOX or BZB, or both, are needed.
Over the last two decades, nanoparticle-mediated drug delivery systems have been demonstrated as effective methods for the targeted delivery of chemotherapeutic drugs, via enhanced permeability and retention (EPR) effects. Encapsulation of cytotoxic anticancer drugs inside a nanoparticle is able to decrease side toxicity and improve the life quality of patient. Various nanocarrier systems have been developed for single drug delivery. However, it has been challenging to encapsulate two drugs with the distinct chemical and physical properties into one nanocarrier, such as hydrophobic PTX and metallic CDDP or polar bortezomib and hydrophobic DOX. Recently, a few studies have reported the co-delivery of CDDP, or Platinum prodrug (Pt-IV) together with other hydrophobic chemodrugs, such as PTX, docetaxel, daunorubicin, and gambogic acid, etc., to improve anticancer effects. However, versatile nanocarriers are still needed to fine tune the drug loading ratio and control the drug release profiles to maximize the synergism of combination therapies, such as PTX and CDDP in combination for treating ovarian cancer.
More and more, targeted therapy has been applied with traditional chemotherapy to achieve synergism in cancer treatments. In addition, gene therapy has been tested in clinic to restore the protein function by knock-in or suppress a mutated protein via gene silencing technique to treat diseases. A very efficient approach is to deliver siRNA to silence the critical proteins related with multiple drug resistance in chemotherapy. Therefore, the combination of therapeutic genes and chemodrugs would achieve synergism in treating cancers. If these two types of drug molecules could be co-delivered to tumor cells selectively with the optimal dose ratio delivered on the right time schedule, the side effects would be reduced and the therapeutic outcome maximized. However, gene molecules are highly water soluble. Moreover, targeted therapeutics, such as tyrosine kinase inhibitor, protesome inhibitor and other targeted inhibitors and antimetabolite drugs, are generally very polar molecules while traditional cytotoxic chemodrugs are generally hydrophobic (e.g., taxanes, anthracycline, vinca alkaloid and camptothecin drugs). It is challenging to co-load a nanoparticle with two types of drug molecules having distinct chemical and physical properties, such as, for example, a hydrophobic with a hydrophilic drug or a hydrophobic with a metallic drug. In addition, the combination delivery of anticancer drugs and gene molecules is a promising strategy to overcome multiple drug resistance. The gene molecules to be delivered could be plasmid DNA molecules for cell transfection of tumor suppressor proteins (e.g., P53, PTEN, etc., or siRNA) to knock down curtain transmembrane efflux protein, or another oncoprotein, such as ABCB1, MDR1, etc., to sensitize cancer cells to chemotherapy. However, the co-delivery of highly negatively charged gene molecules with a given chemodrug having its own distinct physic-chemical properties is still challenging. A novel functionalized and spatially segregated nanocarrier is needed to refine the loading properties of different drug molecules within one depot. Once developed, these nanocarriers could be applied in the co-delivery of a broader range of gene molecules, hydrophilic, amphiphilic, metal-containing, and hydrophobic drug molecules.